Hypertension (HTN) contributes disproportionately to the global burden of disease. In our prior application, we have provided evidence for an important link between particulate matter <2.5 mm (PM2.5) exposure and development of HTN. In this competitive renewal application, we propose to further investigate these links in the context of our findings that inflammation mediated sympathetic nervous system (SNS) activation in circumventricular organs (CVO) in the brain represent an integrative mechanism for PM2.5 induced HTN. Our hypothesis is consistent with an evolving shift in our understanding of the SNS as an arbitrator of acute tonal changes in HTN to a facilitator of chronic functional and structural changes via immune mechanisms. We propose to test this hypothesis in both animal models and humans as part of our established inter-disciplinary collaborative group. In aim 1, we will investigate the time course, loci and impact of central nervous system (CNS) inflammation on BP with PM2.5 exposure conducted in a versatile aerosol concentration enrichment system (VACES) using C57/Bl6 and NFkB reporter mice. We will directly assess the impact of PM2.5 in exaggerating BP using a model of central SNS activation and also assess the impact of activating inflammation proximally on SNS activation on BP response to FA/PM2.5. Dose response studies and analysis of PM2.5 components responsible for HTN, will be performed in pre-disposed models. In Aim 2, the role of central TLR activation in the CVO organs will be tested by deleting TNF receptor-associated factor (TRAF6), selectively in the CVO using UbcCre-TRAF6flox/flox(TRAF6pCNS) mice using Tamoxifen injected intra-cerebroventricularly (ICV), followed by exposure to FA/PM2.5. TRAF6 is a unique member of the TRAF family that functions at nodal points where signals induced via multiple TLRs converge. We will additionally distinguish between neuronal and glial cell specific role of TRAF6 in CNS inflammation in response to PM2.5. In Aim 3, we will test the involvement of central SNS as a relevant pathway in humans, exposed to sub-acute time periods to ambient PM2.5, as part of a blinded randomized cross-over intervention. Our hypothesis is that Guanfacine an approved a2A agonist will obviate the association of ambient PM2.5 with 24-hour ambulatory systolic BP and SNS activity measured by HRV measures. Our experiments are highly relevant to continuing risk posed by air- pollution to people living in urbanized environments.